Noninvasive Imaging of Myocardial Ischemia docx

Noninvasive Imaging of Myocardial Ischemia
Constantinos D. Anagnostopoulos,
Jeroen J. Bax, Petros Nihoyannopoulos
and Ernst van der Wall (Eds)
Noninvasive Imaging of
Myocardial Ischemia
With 129 Figures
Including 45 Color Plates
Constantinos D Anagnostopoulos, MD, PhD, FRCR, FESC
Royal Brompton Hospital and
Chelsea & Westminster Hospital, London, UK, and
National Heart and Lung Institute, Imperial College School of Medicine, London, UK
Petros Nihoyannopoulos, MD, FRCP, FACC, FESC
Imperial College, Hammersmith Hospital, London, UK
Jeroen J. Bax, MD, PhD
Leiden University Medical Center, Leiden, The Netherlands
Ernst van der Wall, MD, FESC, FACC
Leiden University Medical Center, Leiden, The Netherlands
British Library Cataloguing in Publication Data
Noninvasive imaging of myocardial ischemia
1. Coronary heart disease – Imaging 2. Diagnostic imaging
I. Anagnostopoulos, Constantinos D.
616.1¢23¢0754
ISBN-10: 1846280273
Library of Congress Control Number: 2005929229
ISBN-10: 1-84628-027-3 e-ISBN: 1-84628-156-3
ISBN-13: 978-1-84628-027-6
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To those who have devoted their lives to
their patients and the art of medicine
“. . . And if you find her poor, Ithake won’t have fooled you. Wise as you will have become,
so full of experience, you will have understood by then what these Ithakes mean.”
Konstantinos Kavafis, Ithake, 1910
Foreword I
ix
Noninvasive cardiac imaging is an integral part of the practice of current clinical cardi-
ology. During the past three decades a number of distinctly different noninvasive
imaging techniques of the heart, such as radionuclide imaging, echocardiography, mag-
netic resonance imaging, and X-ray computed tomography have been developed.
Remarkable progress has been made by each of these technologies in terms of technical
advances, clinical procedures, and clinical applications/indications. Each technique was
propelled by a devoted group of talented and dedicated investigators who explored the

potential value of each technique for making clinical diagnoses and for defining clinical
characteristics of heart disease that might be most useful in the management of patients.
Thus far, most of these clinical investigations using various non-invasive cardiac imaging
techniques were conducted largely in isolation from each other, often pursuing similar
clinical goals. There now exists an embarrassment of riches of available imaging tech-
niques and the potential for redundant imaging data. However, as each noninvasive
cardiac imaging technique matured, it became clear that they were not necessarily
competitive but rather complementary, each offering unique information under unique
clinical conditions.
The development of each technique in isolation resulted in different clinical sub-
cultures, each with its separate clinical and scientific meetings and medical literature.
Such a narrow focus and concentration on one technology may be very beneficial during
the development stage of a technology, but once the basic practical principles have been
worked out and clinical applications are established, isolation contains the danger of
duplication of pursuits and scientific staleness when technology limits are reached. It
should be obvious that each technique provides different pathophysiologic and/or
anatomic information. Coming out of the isolation and cross-fertilization is the next
logical step to evolve to a higher and more sophisticated level of cardiac imaging.Patients
would benefit tremendously if each technique were to be used judiciously and dis-
criminately, and provided just those imaging data needed to manage a specific clinical
scenario. I anticipate that in the future a new type of cardiac imaging specialist will
emerge. Rather than one-dimensional subspecialists, such as (I apologize) nuclear car-
diologists or echocardiographers, multimodality cardiac imagers will be trained who
have in-depth knowledge and experience of all available non-invasive cardiac imaging
techniques. These imaging specialists will fully understand the value and limitations of
each technique and will be able to apply each of them discriminately and optimally to
the benefit of cardiac patients.
In Noninvasive Imaging in Myocardial Ischemia, the editors Drs. Anagnostopoulos,
Nihoyannopolos, Bax, and Van der Wall, provide a wealth of information on the clinical
value of various noninvasive cardiac imaging techniques. The editors collaborated with

a distinguished group of authors – each recognized experts in their particular area of
cardiac imaging. This book not only provides the reader with the present state of the art
of currently available noninvasive cardiac imaging techniques, but also the comparative
value (as far as information is available) of various techniques in different clinical
x Foreword I
conditions and in different patient groups. After a general introduction to the patho-
physiology of coronary artery disease as it relates to cardiac imaging, the first six chap-
ters discuss the basic principles and technology of echocardiography, cardiac magnetic
resonance imaging, radionuclide myocardial perfusion imaging, and computed X-ray
tomography. Subsequent chapters deal with specific clinical conditions for which non-
invasive cardiac imaging may be used. Unique to this book is that in each chapter the
available evidence by alternative imaging techniques is discussed. In some chapters
(Chapters 9–12), this consists merely of a comparison of stress radionuclide imaging and
stress echocardiography, since no data are available for other imaging techniques. In
other chapters (Chapters 7, 8, 13–15) data from the full spectrum of noninvasive cardiac
imaging is available, and the authors discuss how it may be utilized to obtain optimal
anatomic and pathophysiologic information relevant for patient management. Several
chapters propose practical algorithms for stepwise testing by various imaging techniques
in different patient cohorts. The editors and authors are to be applauded for their effort
to come to grips with the difficult task of sorting out the relative and complementary
value of each imaging technique. It is clear that much is not (yet) known and much work
is still to be done. This well-illustrated and well-referenced book is a first step to clini-
cal multimodality cardiac imaging and should be an invaluable resource for anyone
interested in cardiac imaging. This book will be an important aid to cardiology fellows,
nuclear medicine and radiology residents, cardiologists, radiologists, and nuclear med-
icine physicians who wish to take the step to multimodality, noninvasive cardiac
imaging.
Frans J. Th. Wackers, MD
Professor of Diagnostic Radiology
and Medicine

Director, Cardiovascular Nuclear Imaging and Stress Laboratories
Yale University School of Medicine
New Haven, CT
USA
Foreword II
xi
Noninvasive Imaging of Myocardial Ischemia provides a comprehensive discussion and
review of the noninvasive myocardial imaging techniques that are currently available to
detect myocardial ischemia and infarction. Topics covered include echocardiography,
cardiac magnetic resonance imaging, myocardial perfusion scintigraphy, positron
emission tomography,and computed tomography.There are also chapters on myocardial
imaging techniques in the evaluation of asymptomatic individuals, prognostic assess-
ments of patients with CAD by noninvasive imaging techniques, and imaging in the
Emergency Department in patients with chest pain. Risk stratification in patients with
coronary heart disease, imaging techniques used to distinguish hibernating from
irreversibly injured myocardium, and myocardial imaging in non-coronary and con-
genital heart disease causes of myocardial ischemia are also discussed in the book. The
chapters are comprehensive, informative, and written by experts in imaging of the
myocardium.
This will be a very useful book for everyone interested in noninvasive myocardial
imaging of ischemic heart disease. However, it will need to be updated with some
frequency as one anticipates future advances with multidetector CT imaging, magnetic
resonance imaging, detection of vulnerable atherosclerotic plaques, stem cell therapies,
and the addition of nanotechnology methods to the evaluation and treatment of patients
with coronary artery disease. Hopefully, the Editors will be able to provide periodic
updates of the information available in this book, as well as of the new developments
one anticipates.
James T. Willerson, MD
President, The University of Texas Health Science Center
President-Elect and Medical Director, Texas Heart Institute

Houston, TX 77030
USA
Preface
xiii
Noninvasive cardiac imaging covers a broad spectrum of investigations including
echocardiography, radionuclide imaging, computed tomography (CT), and magnetic
resonance imaging (MRI). Major developments have occurred in this field recently and
imaging data are now utilized almost on a daily basis for clinical decision making.
This book tries to capture the important advances and new directions in which the
field is heading. It provides a forum for a fertile discussion on the strengths and limita-
tions of the various imaging modalities in different clinical settings offering also prac-
tical recommendations for their appropriate use. It focuses on the interrelations and
complimentary roles of different techniques thus reflecting the multifaceted manifesta-
tions of myocardial ischemia.
It is our belief that the field of noninvasive cardiac imaging can only advance and
strengthen its role in the decision-making process when comprehensive evidence-based
information is used.We are very privileged that the contributors to this volume are inter-
national opinion leaders in their field. They have made every effort not only to provide
state of the art information on their respective topics but also to keep alive the discussion
on imaging as a whole. We hope that the book will be a very helpful reference for practi-
tioners from different background and disciplines including cardiologists, general
physicians and imagers.
The first section (Chapters 1 to 6) discusses principles of pathophysiology relevant to
noninvasive cardiac imaging and provides up to date information on the technical
aspects of different imaging modalities. The second section (Chapters 7 to 15) focuses
on the role of imaging in the assessment of myocardial ischemia offering valuable
information on diagnostic and management issues, both within the stable and acute
clinical setting. The accompanying CD contains 10 clinical cases and is designed to
provide examples illustrating the clinical usefulness of noninvasive cardiac imaging in
every day practice.

In a multi-authored book covering topics which are related to each other, a degree of
overlap is inevitable.Every effort has been made to keep that to a minimum whilst main-
taining at the same time the autonomy and completeness of each chapter.
We are indebted to all the contributors for their hard work and commitment to achieve
this delicate balance and we wish to thank all of them for their superb chapters. We are
very grateful to the staff of our departments for their contribution to the presentation
of the images and cases of this book, to all those who supported our work and to the
staff of Springer for their assistance and editorial advice.
C. Anagnostopoulos
J.J. Bax
P. Nihoyannopoulos
E. Van der Wall
Contents
List of Contributors xvii
1 Principles of Pathophysiology Related to Noninvasive Cardiac Imaging
Mark Harbinson and Constantinos D. Anagnostopoulos 1
2 Echocardiography in Coronary Artery Disease
Petros Nihoyannopoulos 17
3 Cardiac Magnetic Resonance
FrankE.Rademakers 37
4 Myocardial Perfusion Scintigraphy
Albert Flotats and Ignasi Carrió 57
5 Positron Emission Tomography
FrankM.Bengel 79
6 Computed Tomography Techniques and Principles.
Part a. Electron Beam Computed Tomography
TarunK.Mittal andMichael B.Rubens 93
6 Computed Tomography Techniques and Principles.
Part b. Multislice Computed Tomography
P.J. de Feyter, F. Cademartiri, N.R. Mollet, and K. Nieman 99

7 Noninvasive Assessment of Asymptomatic Individuals at Risk of
Coronary Heart Disease. Part a
E.T.S. Lim, D.V. Anand, and A. Lahiri 107
7 Noninvasive Assessment of Asymptomatic Individuals at Risk of
Coronary Heart Disease. Part b
Dhrubo Rakhit and Thomas H. Marwick 137
8 Diagnosis of Coronary Artery Disease
Eliana Reyes, Nicholas Bunce, Roxy Senior, and
Constantinos D. Anagnostopoulos 155
9 Prognostic Assessment by Noninvasive Imaging.
Part a. Clinical Decision-making in Patients with Suspected or Known
Coronary Artery Disease
Rory Hachamovitch, Leslee J. Shaw, and Daniel S. Berman 189
xv
9 Prognostic Assessment by Noninvasive Imaging.
Part b. Risk Assessment Before Noncardiac Surgery by Noninvasive Imaging
Olaf Schouten, Miklos D. Kertai, and Don Poldermans 209
10 Imaging in the Emergency Department or Chest Pain Unit
Prem Soman and James E. Udelson 221
11 Risk Stratification after Acute Coronary Syndromes
George A. Beller 237
12 Role of Stress Imaging Techniques in Evaluation of Patients Before and
after Myocardial Revascularization
Abdou Elhendy 247
13 Imaging Techniques for Assessment of Viability and Hibernation
ArendF.L.Schinkel,DonPoldermans,AbdouElhendy,andJeroenJ.Bax . . 259
14 Myocardial Ischemia in Conditions Other than Atheromatous
Coronary Artery Disease
Eike Nagel and Roderic I. Pettigrew 277
15 Myocardial Ischemia in Congenital Heart Disease:

The Role of Noninvasive Imaging
J.L. Tan, C.Y. Loong, A. Anagnostopoulos-Tzifa, P.J. Kilner,
W. Li, and M.A. Gatzoulis 287
Index 307
Various Case Reports on CD-ROM Inside back cover
xvi Contents
Constantinos D. Anagnostopoulos, MD,
PhD, FRCR, FESC
Royal Brompton Hospital
and Chelsea & Westminster Hospital
and Imperial College School of
Medicine
London, UK
A. Anagnostopoulos-Tzifa M.D,
MRCPCH
Guy’s & St Thomas’ Hospital
London, UK
Jeroen J. Bax, MD, PhD
Leiden University Medical Center
Leiden, The Netherlands
George A. Beller, MD
University of Virginia Health System
Charlottesville, VA, USA
Frank M. Bengel, MD
Nuklearmedizinische Klinik der TU
München
München, Germany
Daniel S. Berman, MD, FACC
Cedars-Sinai Medical Center
Los Angeles, CA, USA

Nicholas Bunce MD, MRCP
St. Georges’ Hospital
London, UK
Filippo Cademartiri, MD, PhD
Erasmus Medical Center
Rotterdam, The Netherlands
Ignasi Carrió, MD
Autonomous University of Barcelona
Hospital de la Santa Creu i Sant Pau
Barcelona, Spain
P.J. de Feyter, MD, PhD
Erasmus Medical Center
Rotterdam, The Netherlands
Vijay Anand Dhakshinamurthy, MBBS,
MRCP
Welli ng ton Ho spi tal
London, UK
Abdou Elhendy MD, PhD
Nebraska Medical Center
Omaha, NE, USA
Albert Flotats, MD
Autonomous University of Barcelona
Hospital de la Santa Creu i Sant Pau
Barcelona, Spain
Michael A. Gatzoulis, MD, PhD
Royal Brompton Hospital
London, UK
Mark Harbinson, MD, FRCP
Queen’s University Belfast
Belfast, Northern Ireland

Rory Hachamovitch, MD, MSc
Keck School of Medicine, U.S.C.
Los Angeles, CA, USA
Miklos D. Kertai, MD
Erasmus Medical Centre
Rotterdam, The Netherlands
Philip J. Kilner, MD, PhD
Royal Brompton Hospital
London, UK
Avijit Lahiri, BS, MB, MSc, MRCP
Welli ng ton Ho spi tal
London, UK
List of Contributors
xvii
W. L i , M D , P h D
Royal Brompton Hospital
London, UK
Eric Tien Siang Lim, MRCP, MA Cantab
Welli ng ton Ho spi tal
London, UK
C.Y. Loong, MBBS, MRCP
Royal Brompton Hospital
London, UK
Thomas H. Marwick, MBBS, PhD,
FRACP, FACC
University of Queensland
Princess Alexandra Hospital
Brisbane, Australia
Tarun K. Mittal, MBBS
Royal Brompton & Harefield Hospital

NHS Trust
London, UK
Niko R. Mollet, MD
Erasmus Medical Center
Rotterdam, The Netherlands
Eike Nagel, MD
German Heart Institute Berlin
Berlin, Germany
K. Nieman, MD, PhD
Erasmus Medical Center – Thoraxcenter
Rotterdam, The Netherlands
Petros Nihoyannopoulos, MD, FRCP,
FACC, FESC
Imperial College London
Hammersmith Hospital, NHLI
London, UK
Roderic I. Pettigrew, PhD, MD
National Institute of Biomedical
Engineering and Biological Imaging
National Institutes of Health
Bethesda, MD, USA
Don Poldermans, MD, PhD
Erasmus Medical Centre
Rotterdam, The Netherlands
Frank E. Rademakers, MD, PhD
University Hospitals Leuven
Catholic University Leuven
Leuven, Belgium
Dhrubo Rakhit, MD
University of Queensland

Princess Alexandra Hospital
Brisbane, Australia
Eliana Reyes, MD
National Heart and Lung Institute
Imperial College
London, UK
Michael B. Rubens, MBBS, DMRD, FRCR
Royal Brompton & Harefield Hospital
NHS Trust
London, UK
Arend F.L. Schinkel, MD
Thoraxcentre
Erasmus Medical Centre
Rotterdam, The Netherlands
Olaf Schouten, MD
Erasmus Medical Centre
Rotterdam, The Netherlands
Roxy Senior, MD, DM, FRCP, FESC,
FACC
Northwick Park Hospital and Institute
for Medical Research
Harrow, Middlesex, UK
Leslee J. Shaw, PhD
Cedars-Sinai Medical Center
Los Angeles, CA, USA
Prem Soman, MD, PhD, MRCP
Tufts-New England Medical Center
and Tufts University School of Medicine
Boston, MA, USA
Ju-Le Tan, MBBS, MRCP

Royal Brompton Hospital
London, UK
James E. Udelson, MD
Tufts-New England Medical Center
and Tufts University School of Medicine
Boston, MA, USA
xviii List of Contributors
This chapter considers the principal mecha-
nisms involved in regulating myocardial blood
flow, and reviews the pathophysiologic changes
observed during myocardial ischemia.A detailed
discussion of the precise biochemical and cellu-
lar mechanisms involved is beyond the scope of
this review, but the basic mechanisms by which
cardiac stress techniques allow interrogation of
the many changes occurring during ischemia are
presented. Although we focus on myocardial
ischemia, strictly speaking, imaging techniques
do not always detect ischemia itself. Changes
in local perfusion accompany ischemia, and
may indeed be induced without frank ischemia
actually developing. It should be recognized,
therefore, that many of the stress techniques dis-
cussed actually precipitate changes in myocar-
dial blood flow as their primary effect.
Hypoxia is frequently defined in terms of a
reduction in tissue oxygen supply despite
adequate perfusion, whereas ischemia addition-
ally implies reduced removal of metabolites
(for example, lactate) attributed to failure of an

appropriate level of perfusion. Hypoxia may
therefore be seen with chronic lung disease or
carbon monoxide poisoning, for example. The
most frequent cause of myocardial ischemia in
humans is coronary atherosclerosis. As well as
being a chronic process associated with coro-
nary luminal narrowing and impaired endothe-
lial function, atherosclerosis is associated with
acute episodes of plaque rupture, coronary
1. Causes of Myocardial Ischemia . . . . . . . . . . . . . 2
1.1 Atherosclerosis . . . . . . . . . . . . . . . . . . . . . . . 2
1.2 Imaging Atherosclerosis . . . . . . . . . . . . . . . 2
1.3 Other Causes of Myocardial
Ischemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
2. The Coronary Circulation . . . . . . . . . . . . . . . . . 3
3. Physiology of Myocardial Oxygen Supply
and Oxygen Demand . . . . . . . . . . . . . . . . . . . . . 4
3.1 Myocardial Oxygen Demand . . . . . . . . . . . . 4
3.2 Myocardial Oxygen Supply . . . . . . . . . . . . . 4
4. Coronary Blood Flow . . . . . . . . . . . . . . . . . . . . . 4
4.1 Metabolic Regulation of Coronary Blood
Flow . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
4.2 Endothelial-dependent Modulation of
Coronary Blood Flow . . . . . . . . . . . . . . . . . . 5
4.3 Autoregulation of Coronary Blood Flow . . . . . 6
4.4 Autonomic Nervous Control . . . . . . . . . . . . 6
4.5 Circulating Hormones . . . . . . . . . . . . . . . . . 6
4.6 Extravascular Compressive Forces . . . . . . . 6
5. Events During Ischemia . . . . . . . . . . . . . . . . . . . 6
5.1 Metabolic and Blood Flow Changes, and

Imaging Findings . . . . . . . . . . . . . . . . . . . . . 6
5.2 Contractile Dysfunction and Imaging
Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
5.3 Electrocardiographic Changes and
Imaging Findings . . . . . . . . . . . . . . . . . . . . 10
6. Consequences of Ischemia . . . . . . . . . . . . . . . . 11
6.1 Myocardial Hibernation and
Stunning . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
6.2 Ischemic Preconditioning . . . . . . . . . . . . . 11
6.3 Ischemia-reperfusion Injury and
No-reflow Phenomenon . . . . . . . . . . . . . . . 12
7. Clinical Phenomena and Their Relation to
Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
8. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
1
Principles of Pathophysiology Related to Noninvasive
Cardiac Imaging
Mark Harbinson and Constantinos D. Anagnostopoulos
1
vasospasm, and thrombosis causing acute coro-
nary syndromes. This chapter deals mainly with
the pathophysiologic effects of chronic athero-
sclerosis, which results in chronic ischemic syn-
dromes such as angina pectoris. Myocardial
ischemia for other reasons or as a result of
nonatheromatous disease processes is not dis-
cussed in detail, although the underlying physi-
ology is similar.
1. Causes of Myocardial Ischemia
In humans, atherosclerosis is by far the most

common cause of acute and chronic ischemic
syndromes. Atherosclerosis, and its imaging, are
briefly reviewed, and, finally, nonatheromatous
causes of myocardial ischemia are discussed.
1.1 Atherosclerosis
Atherosclerosis is a chronic condition character-
ized by deposition of cholesterol-laden plaques
and inflammatory cells in the vascular wall. The
chronic expansion of plaques can lead to the
development of flow-limiting coronary stenoses,
which are associated with angina pectoris. It is
therefore the main disease process underlying
angina and hence the main target for imaging.
It is punctuated with acute episodes of plaque
instability leading to acute coronary syndromes
including myocardial infarction.
It is thought that lipid accumulation in the
arterial wall is one of the first stages in the devel-
opment of atherosclerotic lesions. Low density
lipoprotein molecules have been identified in the
arterial wall and once bound there are suscepti-
ble to modification, with oxidation believed
to be particularly important.
1
Leukocytes are
then recruited to the area and enter the intima.
Monocytes accumulate the lipid deposited in the
intima and become characteristic “foam cells.”
2
The earliest macroscopic change in atheroscle-

rosis, the “fatty streak,” consists largely of lipid-
laden foam cells.After the formation of this basic
lesion, atheroma then progresses chronically
over some time period, with an increase in
vascular smooth muscle and extracellular matrix.
At first, the artery expands outward rather than
inward, i.e., the whole cross-sectional area of the
vessel increases and the lumen is little changed.
3
As the vessel continues to enlarge, however, the
lumen then begins to be compromised. This may
lead to chronic stable angina, and demonstration
2 Noninvasive Imaging of Myocardial Ischemia
of coronary flow limitation related to such stenotic
plaques is central to noninvasive assessment
of ischemic heart disease.
Besides this chronic progressive increase,
sudden changes in plaque size and morphology
have been noted, and may occur silently or be
manifest as an acute coronary syndrome. The
main processes are acute plaque rupture
4
or
acute plaque erosion,
5
and then subsequent
thrombosis. It has been suggested that plaques
mainly composed of lipid with a thin fibrous cap
(“soft plaques”) are more liable to rupture and
hence precipitate acute coronary syndromes,

whereas plaques with less lipid and better-
formed fibrous caps are more stable and tend to
cause chronic angina rather than acute vessel
occlusion.
6
Atherosclerotic plaques are ubiquitous as age
advances, but several risk factors for earlier
development of atheromatous coronary artery
disease have been identified. Nonmodifiable risk
factors include advancing age, male gender,
and genetic factors, often described in terms
of family history of premature onset disease.
Modifiable risk factors include hyperlipidemia,
hypertension, cigarette smoking, and diabetes
mellitus.
1.2 Imaging Atherosclerosis
Beyond the more conventional imaging strategies
assessing myocardial perfusion, that is, the func-
tional consequence of coronary stenosis, several
techniques are now available to image atheroma
itself. These are briefly described below.
Intravascular ultrasound catheters can be
delivered directly into the coronary arteries
and an ultrasound image of the circumferential
extent and composition of plaques can be
obtained. This can be useful in assessing the
anatomy before and after percutaneous coronary
intervention and may be helpful in defining the
extent and severity of lesions noted on X-ray
coronary arteriography. Doppler ultrasound can

also be used to measure the velocity of blood
flow in the coronary arteries. This can then be
measured before and after areas of stenosis,
compared with proximal blood flow, and with
blood flow after maximum pharmacologic
vasodilatation. Hence, the functional signifi-
cance of lesions can be assessed. A similar tech-
nique uses pressure rather than Doppler velocity
measurement.
7
of patients is rather heterogeneous, but, in
some cases, ischemia has been demonstrated.
13
In these cases, dysfunction of the micro-
vascular circulation has been identified.
14
Indeed, assessment of myocardial perfusion
using magnetic resonance techniques has shown
that an abnormal gradient develops between
subepicardial and subendocardial perfusion
during vasodilator stress with adenosine.
15
Not
all patients with putative syndrome X have
evidence of ischemia, however, and the group
may also include patients with alternative causes
for chest pain or with abnormal sensitivity to
pain.
Coronary spasm may also cause chest pain
similar to angina. Spasm may occur on athero-

sclerotic plaques in the coronary vessels,but also
in patients without apparent atherosclerotic
coronary disease. Variant or Prinzmetal’s angina
causes chest pain at rest and may be associated
with ST segment elevation on the 12-lead elec-
trocardiogram (ECG).
16
Coronary arteriography
has demonstrated coronary artery spasm in
these patients, and perfusion defects have been
reported.
17
Abnormal resting coronary tone and
abnormalities of resting sympathetic coronary
innervation have also been suggested as possible
etiologic factors.
It should be clear, therefore, that the finding of
a perfusion defect during cardiac stress should
not always lead to the conclusion that athero-
sclerotic coronary disease is the underlying
cause.
2. The Coronary Circulation
Blood is delivered to the heart by the right and
left coronary arteries, which arise normally from
the aortic sinuses immediately above the aortic
valve. The heart is a very active metabolic organ
and requires a high level of oxygen delivery.
Furthermore, oxygen extraction from delivered
blood is high even at rest.Any increase in oxygen
demand, therefore, must be met by increasing

coronary blood flow, because there is little scope
to increase oxygen extraction. To meet this level
of oxygen demand, resting coronary blood flow
is relatively high compared with other arteries,
resting oxygen extraction is high, and the distri-
bution of capillaries in the myocardium is dense.
In addition, the coronary vessels are essentially
end-arteries. Taken together with this high
metabolic demand, these factors mean that the
More recently, magnetic resonance imaging
(MRI) has been used to assess atheromatous
plaques including those in coronary arteries. The
use of different sequences, including contrast
agents, has demonstrated plaque morphology
including the lipid pool. This has led to the sug-
gestion that similar methods might be able to
characterize plaque composition and differenti-
ate “vulnerable” from stable lesions.
8
Multislice
computed tomographic images of the coronary
arteries are now almost of a similar standard
to X-ray angiography in many patients.
9
Simi-
larly, early reports on the application of 18-
fluorodeoxyglucose have been presented.
10
This
tracer localizes to areas of metabolic activity,

and can be detected with positron emission
tomographic (PET) technology. Using coregis-
tration with anatomic images, it is possible that
active or vulnerable plaques may be identified
and differentiated from more metabolically qui-
escent plaques with in theory a lower propensity
to rupture. Several other approaches to imaging
the pathophysiologic processes underlying athe-
rosclerosis are currently being investigated.
11
These include imaging of vascular smooth
muscle cells (using the labeled antibody Z
2
D
3
)
and of the inflammatory processes within the
vessel wall (for example, using radiolabeled
matrix metalloproteinase). Similarly, apoptosis,
the process of programmed cell death, can
be imaged using 99m-technetium-labeled
annexin V. Apoptosis of macrophages is seen in
active atherosclerotic plaques, and also in the
myocardium in acute myocardial infarction;
annexin V uptake has been demonstrated in
human myocardial infarction.
12
1.3 Other Causes of Myocardial Ischemia
Although the vast majority of patients with
angina have coronary atherosclerosis, other eti-

ologies are recognized (see also Chapters 14 and
15). Problems with blood oxygen-carrying
capacity, and with increased demand as a result
of ventricular hypertrophy, may cause ischemia
in the absence of what would normally be
considered severe flow-limiting coronary
stenoses (see below). The most common causes
of ischemia beyond the atheromatous coronary
disease are discussed in Chapters 14 and 15.
Syndrome X is a clinical entity characterized
by anginal chest pain but unobstructed epicar-
dial coronary arteries at angiography. This group
Principles of Pathophysiology 3
heart is relatively susceptible to ischemia and
infarction.
3. Physiology of Myocardial Oxygen
Supply and Oxygen Demand
The balance between myocardial oxygen re-
quirements, and oxygen delivery, is central
to understanding the mechanisms by which
ischemia may occur. This balance is upset spon-
taneously during attacks of angina and other
clinical manifestations of ischemia, and can be
manipulated by various maneuvers during
cardiac stress. An unmet increase in oxygen
demand, a reduction in oxygen supply, or a com-
bination of both can cause myocardial ischemia.
3.1 Myocardial Oxygen Demand
Cardiac oxygen requirements depend on a
variety of parameters.

18
In the acute situation, it
is mainly cardiac work that is important. This is
determined by both heart rate and blood pres-
sure, and their overall effect may be assessed
as the rate-pressure product (RPP).
19
This is
strongly correlated with myocardial oxygen con-
sumption; therefore, an increase in RPP causes
an increase in oxygen demand which, if not met
by compensatory mechanisms, leads to myocar-
dial ischemia. This is the parameter most fre-
quently targeted by cardiac stress, with dynamic
exercise and also to some extent with dobuta-
mine stress, acting to increase RPP and hence to
precipitate myocardial ischemia.
Myocardial wall tension may also change
fairly rapidly and is an important determinant
of myocardial oxygen demand. An increase in
ventricular volume will be associated with
an increase in wall tension and then usually
increased velocity of contraction. This extra
work requires additional oxygen supply.
Other significant determinants of myocardial
oxygen requirements are of less importance in
the context of this chapter because they usually
are not amenable to direct manipulation during
cardiac stress. The inotropic status of the
myocardium and overall cardiac mass are

the other parameters of significance. As the
inotropic status of the heart is augmented, the
energy requirements for this active process
increase, and hence oxygen demand increases.
4 Noninvasive Imaging of Myocardial Ischemia
Although cardiac mass does not change acutely,
patients with ventricular hypertrophy are pre-
disposed to myocardial ischemia because of
increased oxygen demand of the additional
myocyte mass.
3.2 Myocardial Oxygen Supply
Oxygen delivery depends on adequately oxy-
genated hemoglobin reaching the myocyte. The
main determinants of myocardial oxygen supply
are therefore the oxygen-carrying capacity of the
blood and coronary blood flow. The former
largely depends on the hemoglobin concentra-
tion, and anemia may precipitate angina in sus-
ceptible patients. Other situations in which
blood oxygen delivery or extraction is inade-
quate, such as CO poisoning, are rare. The latter,
namely, coronary blood flow, depends on two
parameters: the driving pressure from the
aorta, and control of coronary vascular tone
(resistance). Aortic diastolic pressure is usually
sufficient to perfuse the coronary artery ostia at
most normal levels of blood pressure and is not
generally a cause of myocardial ischemia. From
the standpoint of stress testing for assessment of
myocardial ischemia in patients, coronary blood

flow, and its relationship to coronary tone, is the
most important parameter to understand. These
factors are briefly summarized in Table 1.1.
4. Coronary Blood Flow
The arterioles and pre-arteriolar vessels consti-
tute the major resistance vessels in the coronary
system.Vasodilatation in this bed increases coro-
nary blood flow and is the main method for
increasing myocardial perfusion. The balance
Table 1.1. Important factors in the control of myocardial oxygen supply
and myocardial perfusion
1. Oxygen-carrying capacity of blood
2. Overall driving pressure (aortic diastolic pressure)
3. Coronary vascular tone/resistance
Metabolic regulation
Endothelium-dependent factors
Autoregulation of blood flow
Autonomic nerves
Circulating hormones
Extravascular compressive forces
blood flow during metabolic activity, and is
released during hypoxia.
23
This is discussed in
more detail later. The ATP-dependent potassium
channel is also activated during ischemia and
causes a local compensatory vasodilatation, as
well as having other effects.
4.2 Endothelial-dependent Modulation of
Coronary Blood Flow

The coronary endothelial lining is metabolically
active and secretes a variety of vasoactive sub-
stances. The balance between dilator and con-
strictor molecules helps to determine overall
coronary tone. Some of these substances are
briefly discussed below.
The substance endothelium-derived relaxing
factor is most important among the vasodilators,
and has been identified as the NO radical.
24
NO
is synthesized from the amino acid
L-arginine by
the enzyme NO synthase. NO is produced con-
tinuously by the epithelium and acts as a potent
vasodilator locally. The main stimulus to local
NO secretion is shear stress, that is, the force
exerted on the endothelial wall by the sliding
action of flowing blood. Under resting circum-
stances, this maintains a low basal NO level. In
the nonresting state, this shear stress-induced
NO release is also important. During exercise,
distal arterioles dilate by a metabolic hyperemia
mechanism (see above). This leads to blood
flow changes in the feeding artery, and to
activation of the shear stress-mediated NO
pathway. In this way, the feeding vessel can dilate
to increase blood delivery to the arteriolar
system. This is an example of flow-mediated
vasodilatation.

Prostacyclin (PGI2) is also a potent vasodila-
tor agent, and has some role in flow-mediated
vasodilatation and metabolic regulation.
25
It is
produced from arachidonic acid by the enzyme
cyclooxygenase. It has a relatively short duration
of action and is not believed to be as important
as NO.
The endothelium also produces vasoconstric-
tor molecules. One such group is the endothelin
family of molecules. The most relevant of the
three forms is endothelin 1. It is synthesized
and released continuously, causing a persistent
and relatively long-acting vasoconstriction.
26
Endothelin 1 therefore counteracts the effects of
NO on basal resting tone.
between vasodilator and vasoconstrictor tone in
this arteriolar bed therefore determines coro-
nary blood flow. Several factors are involved in
this balance (Table 1.1) and are discussed in
turn. Many noninvasive methods, therefore,
interrogate the perfusion system rather than
induce ischemia itself.
4.1 Metabolic Regulation of Coronary
Blood Flow
An important local method for regulating coro-
nary blood flow is termed metabolic hyperemia.
Any increase in metabolic activity, for example,

exercise, leads to a release of chemical sub-
stances into the local interstitial fluid. These sub-
stances cause a vasodilatation of the arterioles
and therefore an increase in local blood flow to
match the increase in metabolic activity. This
metabolic hyperemia is carefully controlled and
studies have shown that blood flow increases
almost linearly with the local tissue metabolic
rate or myocardial oxygen consumption.
18
Several substances may be involved in the
process; some of these are briefly mentioned
below.
Adenosine is a potent vasodilator and is
produced by hypoxic myocytes. It is probably
the most important effector molecule in coro-
nary metabolic regulation.
20
During hypoxia and
ischemia, adenosine monophosphate is formed
by the degradation of the high-energy phosphate
adenosine triphosphate (ATP). Adenosine is
then generated by the action of the enzyme
5¢ nucleotidase on adenosine monophosphate.
Adenosine acts as a powerful vasodilator.Adeno-
sine therefore seems to be linked to the vasodi-
latation and reduction in coronary vascular tone
observed during ischemia.
21
Because of this

strong vasodilatory effect, exogenous adenosine
may be administered as a pharmacologic stress
agent. It causes an increase in blood flow in
normal vessels of at least four-fold.
22
Because
areas subtended by a resting stenosis already
have utilized these metabolic mechanisms to
maintain a normal blood flow at rest, further
dilatation is substantially less or even absent, and
flow heterogeneity is generated.
Although adenosine is believed to be the most
important mediator of metabolic flow regula-
tion, other substances may have a part. The
potent vasodilator nitric oxide (NO) increases
Principles of Pathophysiology 5
Endothelial control of coronary vasodilator
tone has received considerable attention because
there is a large body of evidence to suggest that
it is compromised in patients with atheroscle-
rotic vascular disease, or indeed with significant
risk factors for it. Indeed, many patients with
atheroma tend to exhibit a relatively vasocon-
strictor basal coronary tone.
4.3 Autoregulation of Coronary Blood Flow
It has been noted that despite significant varia-
tions in the driving (diastolic) aortic perfusion
pressure, there is little or only very transient
change in myocardial perfusion. This is termed
autoregulation.

27
It is important as a compensa-
tion for minute-to-minute variations in diastolic
blood pressure, and also in patients with epicar-
dial coronary stenoses. In the latter, coronary
perfusion is maintained partly because of adap-
tation (namely, vasodilatation) in the resistance
vessels. This explains why patients with signi-
ficant coronary stenoses do not usually experi-
ence angina at rest and do not have evidence of
perfusion abnormalities during resting myocar-
dial perfusion (e.g., nuclear) studies. During
stress or increased metabolic demand, however,
this is not the case. The relative increase in blood
flow in stenotic arteries with exercise is greatly
reduced compared with normal arteries, which
have not yet exhausted this compensatory mech-
anism. The difference between coronary blood
flow at rest and after maximal vasodilatation is
termed coronary flow reserve.
28
The mecha-
nisms that underlie coronary autoregulation are
unclear but may again involve NO. It has recently
been shown that autoregulatory changes in
arteriolar blood volume can be measured by
myocardial contrast echocardiography.
29
4.4 Autonomic Nervous Control
Overall neural control of coronary tone is prob-

ably not as important as the factors discussed
above.Vasoactive nerves are autonomic and have
sympathetic or parasympathetic effects.
30
Acti-
vation of parasympathetic nerves results in
vasodilatation. Sympathetic nerve activity may
produce either a dilating (beta-2 receptor) or
constricting (alpha receptor) effect. Although
these are significant effectors, they have rela-
tively little part in the pathophysiology of non-
6 Noninvasive Imaging of Myocardial Ischemia
invasive imaging, except perhaps during exercise
and dobutamine stress, and are not discussed in
detail.
4.5 Circulating Hormones
General control mechanisms, which have wide-
spread effects throughout the body, can still
exert a significant influence on coronary blood
flow. Various circulating hormones exert a gen-
eralized effect on arteriolar tone, and therefore
coronary tone in addition. Catecholamine secre-
tion has been well studied. Noradrenaline has
a vasoconstrictive effect largely mediated via
alpha receptors. Adrenaline has high affinity
for beta-2 receptors and often therefore causes
predominantly a vasodilatation. Of course,
catecholamines have other effects on heart rate
and inotropy that are relevant in the develop-
ment of ischemia. Other circulating hormones,

including vasopressin and angiotensin II, are
vasoconstrictors.
4.6 Extravascular Compressive Forces
Coronary blood flow is predominant during
diastole. This is because, during left ventricular
contraction (i.e., systole), intramyocardial
vessels are compressed and deformed, and con-
sequently blood flow is compromised and often
halted completely. In addition, the intraventric-
ular systolic pressure exerts an adverse effect on
subendocardial blood flow.
5. Events During Ischemia
The pathophysiologic events underlying
ischemia have been described in terms of a
“cascade.”
31
This is a useful concept because it
allows the various imaging and stress modalities
to be correlated with the pathophysiologic mech-
anisms. A brief summary is given in Table 1.2.
5.1 Metabolic and Blood Flow Changes, and
Imaging Findings
As alluded to above, as myocardial oxygen
demand increases or coronary blood flow
decreases, autoregulatory and metabolic regula-
tory mechanisms become active to try to main-
tain myocardial perfusion at a normal level.
derived vasodilator mechanisms. The first
abnormality to be apparent during ischemia is
therefore reduced perfusion to the affected ter-

ritory. It is not until a diameter stenosis of
approximately 80% that resting perfusion is
finally reduced, and certainly any stenosis less
than 50% diameter is unlikely to have any hemo-
dynamic consequences even during maximum
coronary dilatation (see Figure 1.1).
34
Patients with reduced perfusion at rest caused
by severe stenotic plaques may present acutely
Metabolic and blood flow changes are therefore
intimately linked.
During myocardial ischemia, multiple com-
plex events occur at a local cellular level. High-
energy ATP is gradually utilized resulting
in an increase in its metabolites, and hence
in adenosine. This subsequently acts as a
vasodilator in an attempt to compensate for the
reduced perfusion. The reduction in high-
energy phosphates also impairs several energy-
requiring metabolic processes in myocardial
cells. Intracellular calcium overload occurs
because of an impairment of active metabolic
processes that regulate sodium and calcium gra-
dients.
32
This may lead to cell injury and death.
ATP-dependent potassium channels are also
active during ischemia and result in potassium
efflux and a shortening in local action potential
duration. This could potentially predispose to

arrhythmias. Various catabolites such as lactate
and hydrogen ions accumulate, and these can
also cause coronary vasodilatation.
33
These compensatory changes (including auto-
regulation and metabolic regulation) become
exhausted and ischemia finally results as
myocardial blood flow decreases.
31
In patients
with atherosclerotic heart disease, compensatory
mechanisms to maintain myocardial perfusion
in the face of significant epicardial stenoses are
already active.Vasodilatation of the distal vascu-
lar bed occurs and pressure gradient across the
stenosis increases. The exhaustion of compen-
satory mechanisms in patients with coronary
disease is also compounded by abnormal
endothelial function and impaired endothelium-
Principles of Pathophysiology 7
Table 1.2. Pathophysiologic events in ischemia and their correlates in imaging and noninvasive testing
Event Frequently used stress correlates Imaging method
Reduced local perfusion/perfusion mismatches Dynamic exercise Usually SPECT
Vasodilator stress, e.g., adenosine will unmask areas of flow SPECT or PET
heterogeneity Contrast echo
MRI with contrast
Regional contractile abnormality Dobutamine-induced wall motion abnormality 2D echocardiography
Novel echo methods, e.g.,TDI
Cardiovascular MRI
Dynamic exercise 2D echocardiography

Electrocardiographic changes Exercise Exercise stress testing
Changes noted with other modalities but not primary abnormality
being sought
Chest pain/angina Exercise Exercise stress testing
Dobutamine pharmacologic stress Stress echo or MRI
The various pathophysiologic changes occurring during ischemia are listed in the left-hand column.Frequently used stress techniques that rely on this mechanism
or are related to it are given in the middle column.The right-hand column indicates the imaging method used for each type of stress.
Perfusion /
blood flow
Percentage epicardial stenosis
50
1000
Figure 1.1. The effects of epicardial coronary artery stenosis (x axis) on myocar-
dial blood flow (y axis). Blood flow at rest (solid line) is little altered until there is
an obstruction of at least 80%. This is due to compensatory mechanisms which
result in dilatation of the coronary resistance vessels, ensuring blood delivery is
maintained even in the face of significant stenosis. Blood flow increases dramat-
ically during exercise or pharmacological vasodilatation (dashed line).It is noted
that the maximal blood flow gradually falls once there is an epicardial stenosis of
around 50%. In patients with coronary disease these vasodilator compensatory
mechanisms are already active at rest and the large increase in blood flow with
exercise or pharmacological stress cannot occur. A large difference in blood flow
at peak stress can therefore be noted between areas subtended by normal and
stenotic arteries. For detailed discussion see text (Based on Gould 33).
with an acute coronary syndrome. In such
patients, resting perfusion abnormalities can be
demonstrated by nuclear cardiology techniques.
A radiotracer is injected during symptoms
and subsequently a myocardial perfusion scan
is obtained using a gamma camera. A sin-

gle photon emission computed tomographic
(SPECT) study is usually performed instead of
planar imaging. This method can accurately
demonstrate active ischemia in patients present-
ing acutely, and has been studied in the emer-
gency department setting.
35
In patients with stenotic plaques but no
reduction in flow at rest attributed to the above
compensatory mechanisms, perfusion abnor-
malities can be induced by stressing the perfu-
sion system. Any further increase in myocardial
oxygen demand will result in ischemia, because
compensatory mechanisms are already maxi-
mally activated. These phenomena are displayed
in Figure 1.1. Exercise stress, combined with
tomographic myocardial perfusion scan, is the
most common way of demonstrating this in clin-
ical practice. The radionuclide involved (either
99m-technetium-labeled tracers or 201-thallium)
is extracted into the myocardium in a flow-
dependent way. During exercise, myocardial
blood flow increases in areas supplied by rela-
tively normal coronary vessels, but there is no
increase in the areas supplied by stenotic ar-
teries. Tracer uptake in ischemic areas is there-
fore reduced compared with areas of normal
perfusion. These differences in regional tracer
uptake on the perfusion scan images reflect this
in a semiquantitative way.

36
Perfusion abnormalities secondary to stenotic
coronary plaques can also be demonstrated
using pharmacologic stress agents. As discussed
earlier, vasodilators such as adenosine are im-
portant in determining myocardial blood flow
during ischemia and at rest. Adenosine can be
infused intravenously and will cause a sig-
nificant increase (at least four-fold) in coronary
blood flow in normal arteries. Because endoge-
nous vasodilators are already active to compen-
sate for coronary stenoses, in affected territories,
there will not be such a significant increase in
flow, creating flow heterogeneity between areas
with normal and impaired blood delivery.
Dipyridamole acts via the adenosine pathway
and has similar effects. The flow heterogeneity
that results from these agents may cause
ischemia, possibly via coronary steal mecha-
nisms, but this is not universal. It is important,
therefore, to appreciate that these techniques
demonstrate flow heterogeneity rather than
ischemia, although the latter may accompany the
blood flow changes, usually if collateral circula-
8 Noninvasive Imaging of Myocardial Ischemia
tion is present. Injection of a suitable tracer
during pharmacologic stress will therefore allow
the identification of territories subtended by
stenotic arteries, in a similar way to exercise
stress.As with exercise,both 99m-technetium and

201-thallium radiotracers are in common usage
for this indication.
36
Technetium agents have the
advantage that they are fixed in the myocardium
after injection, giving a “snapshot” of perfusion at
the time of injection. This is convenient for sub-
sequent imaging. (These techniques are discussed
in great detail in Chapters 4 and 8.)
Less commonly, positron-emitting tracers can
be injected and imaged using PET systems.
Agents such as H
2
15
O,
13
NH
3
, or Rubidium 82 are
used for this purpose.
37
These are mainly used for
research purposes because they require genera-
tion in a cyclotron and have very short half-lives.
More recently, other imaging methods have
been combined with pharmacologic stress to
assess coronary perfusion. Transpulmonary
bubble contrast agents have been developed for
use with echocardiography. These microbubbles
are injected intravenously and are small enough

to pass through the pulmonary circulation
without significant degradation and eventually
appear on the left side of the heart. They can be
visualized as they appear in the myocardial cap-
illaries. Several protocols can be used. The most
common is to measure how long it takes for con-
trast agent to appear in the myocardium at rest
and during pharmacologic stress with, for
example, adenosine. This is a function of
myocardial perfusion. One method is to inter-
mittently destroy the bubbles by disrupting
them with a high-power (large mechanical
index) ultrasound pulse.
38
The time taken for
fresh contrast to wash in to the myocardium can
be measured and perfusion assessed. This tech-
nique, for example with dipyridamole stress, has
identified coronary artery disease with good
sensitivity and specificity in patients with heart
failure.
39
Cardiovascular MRI can also be used to assess
myocardial perfusion using the same underlying
principles. Most techniques are based on first-
pass perfusion analogous to the echocardio-
graphic method outlined above. Vasodilator
stress is usually performed with adenosine, and
the contrast agent gadolinium given intra-
venously.

40
In most sequences, an inversion
recovery pulse is used to null the myocardium
and the wash-in of gadolinium is then observed.
The first-pass perfusion images obtained can be
observed qualitatively, or semiquantitatively
by examining the wash-in curves and peak
signal intensity.
41
(See also Chapters 2 and 3,
respectively.)
several hours. This period of prolonged, but
reversible, contractile dysfunction after a period
of significant ischemia has been termed myocar-
dial stunning.
45
It can be observed after pro-
longed ischemia as a result of stable or unstable
angina, after myocardial infarction, and after
percutaneous coronary intervention.
46
These contractile images can be imaged
clinically using cardiac ultrasound.
Echocardiography may be utilized in patients
with acute coronary syndromes. Regional wall
abnormalities demonstrated during chest pain
may help in the diagnosis of ischemia, ventricu-
lar function can be assessed, and complications
such as ischemic mitral regurgitation can be
detected. Echocardiography also allows visual-

ization of the development of regional wall
motion abnormalities with stress and detects
ischemia in this way; this is the basis of stress
echocardiography. The development of hypoki-
nesia in a normally contracting segment, or
worsening of function in an already hypokinetic
segment, implies stress-induced ischemia.
Compensatory hyperkinesis in nonischemic
segments or ventricular dilation may also
be observed during the stress test; the latter
suggests multivessel coronary artery disease.
Echocardiography can be performed with exer-
cise,
47
but usually is performed after dobutamine
infusion.
48
Dobutamine increases myocardial
oxygen demand by increasing heart rate and
blood pressure and hence RPP. Atropine may be
added to increase the tachycardia further if no
contractile changes are noted or the increase in
heart rate is insufficient at a dobutamine dose of
40 mg/kg/min. In general, each myocardial
segment is assessed using the standard echo
views. Some authors have suggested that this is
a rather late sign of ischemia, and that long axis
function should be investigated. M mode exam-
ination of the amplitude of long axis contrac-
tion, and its rate of change, can be measured and

in some series correlates relatively well with
ischemia detected using more traditional tech-
niques.
49
An alternative is to use vasodilator
stress, typically with dipyridamole, and attempt
to demonstrate ischemia-related regional wall
changes secondary to changes in coronary blood
flow.
50
As alluded to above, perfusion may now
be assessed by echocardiography and may
replace or complement this traditional strategy.
Currently, the newer technologies such as tissue
Doppler imaging (TDI) are being applied to the
detection of ischemia.
51
TDI measures changes
in regional velocities in different myocardial seg-
ments and may therefore be more sensitive than
observing hypokinesia by traditional methods.
One potential hazard in interpretation of wall
motion abnormalities is the traction of akinetic
5.2 Contractile Dysfunction and
Imaging Findings
The second main event to occur during ischemia
is contractile dysfunction.
42
Again,there is a tem-
poral progression in the abnormality.Initially the

changes occur in a regional manner in the terri-
tory involved, but, as the insult worsens, there is
global impairment of left ventricular function.
Both diastolic and systolic abnormalities occur
during ischemia.Calcium is required for myocar-
dial contraction, and, as indicated above, intra-
cellular calcium handling may be impaired
during ischemia; this may partially explain the
contractile abnormalities observed.
Ischemia results in a regional reduction in sys-
tolic contraction. Contractile function requires
adequate oxygen delivery, and clearly this is
impaired as perfusion is compromised. Hypoki-
nesia, akinesia, and eventually dyskinesia can be
observed in the myocardial segments in the
ischemic territories.
43
Subendocardial myocar-
dial fibers are more sensitive to ischemia than
epicardial fibers, because they lie further from
the epicardial coronary vessels. The subendocar-
dial fibers generally lie in a longitudinal (or long
axis) orientation, and therefore contractile dys-
function may first be observed in this axis. Sub-
sequently, as the ischemia spreads to involve the
transmural extent of the myocardium, contrac-
tile dysfunction spreads to involve the transverse
or short axis fibers. As the extent of the ischemic
territory increases, global ventricular dysfunc-
tion results. Stroke volume, cardiac out-put, and

left ventricular ejection fraction all decrease.
44
Left ventricular failure or cardiogenic shock
result in severe cases.Global systolic dysfunction
is therefore a late sign of myocardial ischemia
and reflects involvement of a large proportion of
the myocardium.
Diastolic dysfunction also occurs during
ischemia, but clinically is rarely targeted for
specific assessment. Ischemia shifts the ventri-
cular end-diastolic pressure-volume relationship
to the left; in other words, for any specific ven-
tricular volume, the end-diastolic pressure is
higher. Ventricular relaxation is also impaired.
These abnormalities together predispose to
pulmonary edema.
Although considered separately, the diastolic
and systolic abnormalities rarely occur as isolated
events in clinical practice. The clinical picture is
therefore usually a combination of increased
ventricular pressure with contractile dysfunction,
presenting as pulmonary congestion or edema if
the extent of ischemia is sufficient.
The contractile abnormalities described fre-
quently do not return to normal immediately
after ischemia is abolished, and may remain for
Principles of Pathophysiology 9
segments by normally contracting neighboring
ones. This may be overcome with TDI by meas-
uring the differences in regional velocities,

and assessing the changes in velocities between
two points (strain and strain rate imaging).
52
Recently, TDI studies have suggested that post-
systolic motion may be an accurate indicator of
ischemia.
53
Nuclear techniques can also be used to
measure regional and global changes in left
ventricular function related to ischemia. Radio-
nuclide ventriculography is a technique for
assessing the left ventricular blood pool. An
injection of technetium-radiolabeled red cells is
given and the counts from the left ventricular
blood pool are obtained using gamma camera
imaging. The use of ECG gating allows deter-
mination of ventricular volume throughout
the cardiac cycle. Both systolic and diastolic
characteristics can therefore be measured
and quantified. Radionuclide ventriculography
imaging can be performed at rest or in combi-
nation with dynamic exercise.
54
Changes in
regional and global function with stress can
therefore be demonstrated.
Alternatively, assessment of regional wall
changes can be performed using gated SPECT-
PET imaging. As discussed above, these studies
are a powerful tools for assessment of myocardial

perfusion. If, however, the images are obtained
with ECG gating, additional information about
regional contractile function can be obtained.
Hence, ischemia-induced functional abnormali-
ties can be obtained from the same study as per-
fusion, with relatively little extra time or cost.
55
In addition, global systolic and diastolic volumes
and ejection fraction at rest and with stress, can
be added to the perfusion data.
56
Stress-induced
chamber dilatation and impairment of systolic
function with stress can also be noted, particu-
larly with exercise stress.
57
Increased lung uptake
of tracer with stress can sometimes be observed,
mainly with 201-thallium.
58
This may well reflect
the increased ventricular pressures, in particular
end-diastolic pressure or pulmonary wedge
pressure (effectively left atrial pressure) alluded
to above. Regional wall abnormalities can also be
sought using dobutamine gated SPECT, rather
than after exercise.
Magnetic resonance techniques again image
regional wall abnormalities induced by stress.
59,60

It is similar to traditional two-dimensional
(2D) echocardiography in this respect. However,
the spatial resolution is excellent, and there
10 Noninvasive Imaging of Myocardial Ischemia
are no limitations of image plane, and poor
nondiagnostic images because of patient phy-
sical factors are rare. The contrast between
endocardium and blood pool in general is also
excellent. Dobutamine stress is mainly used
because of the limitations of physical exercise in
the magnet, although the latter has been used in
some centers. A brief summary of frequently
performed tests is given in Table 1.2.
5.3 Electrocardiographic Changes and
Imaging Findings
Electrocardiographic abnormalities occur late
in the ischemic cascade, and in general are
related to electrical changes in the ischemic
myocardium. The mechanisms by which these
phenomena occur are currently incompletely
understood. During ischemia, the action poten-
tial duration in the ischemic territory is reduced.
Ion channels, such as the ATP-sensitive potas-
sium channel, are activated. As a result, various
electrical gradients are created, and ST segment
change is observed. This results in ST segment
depression, which is the ECG hallmark of acute
myocardial ischemia. Other ECG manifestations
of acute ischemia include T wave changes (which
are not specific) and alterations in R wave ampli-

tude.
During acute coronary occlusion, the ST
segment usually becomes increased. There are at
least two postulated mechanisms for this.
61
The
diastolic injury current theory supposes that the
regional injury is associated with a flow of
current from the uninjured to the affected area.
This causes depression of the TQ segment,which
after correction for the resulting baseline change
on the ECG, appears as ST segment elevation.
The systolic injury current theory supposes that
the injured area undergoes early repolarization.
Current therefore flows from the injured to the
uninjured area during the period of the ST
segment, causing its increase. Because of the
electrical characteristics of the ECG record,
ischemic ST segment depression and elevation
may be seen at the same time in different leads,
or in a reciprocal manner.
Ischemia may also cause arrhythmias. Ven-
tricular arrhythmias may be precipitated by the
electrochemical changes that occur during
ischemia. Activation of ATP-sensitive potassium
channels during ischemia shortens action
dysfunction, associated with significant coro-
nary artery disease, which can be reversed by
revascularization; the definition is therefore ret-
rospective. The time of functional recovery after

revascularization is very variable with improve-
ment noted even some months after inter-
vention.
63
The pathophysiology of chronic
myocardial hibernation is not completely
known. Some studies have noted reduced resting
coronary blood flow to hibernating segments
64
;
this suggests that myocardial contractile func-
tion is “downgraded” to match the reduced per-
fusion supply. Other studies have found that the
reduction in blood flow is minimal, although
there may be exhausted coronary flow reserve.
65
In this situation, it is postulated that recurrent
episodes of ischemia result in hibernation by
causing repetitive myocardial stunning. Cer-
tain characteristics of potentially hibernating
myocardium have been targeted by imaging
methods and will be considered in more detail
in Chapter 13. In general, it is mandatory to
demonstrate regional contractile dysfunction
and evidence that the area concerned is alive
or “viable” and ischemic. This is frequently
assessed by nuclear cardiology techniques,
66
although other methods are available. Resting
201-thallium, 99m-technetium (using SPECT

imaging), or 18-fluordeoxyglucose uptake (us-
ing PET imaging) usually identifies viable
myocardium. Reduced blood flow may be
demonstrated by PET using flow tracers, and a
mismatch between reduced resting flow, but
intact or even increased metabolic activity
detected by 18-fluordeoxyglucose is said to be a
sensitive finding. Improvement in contractile
function with low-dose dobutamine (“contrac-
tile reserve”) followed by worsening of function
at a higher dose (biphasic response) also pre-
dicts improvement after revascularization.
Dobutamine can be combined with either
echocardiography or MRI. Each method has its
own characteristics
67,68
and will be reviewed in
Chapter 13.
6.2 Ischemic Preconditioning
As discussed above, a prolonged and severe
episode of myocardial ischemia leads to
mechanical dysfunction, which can continue for
some time after blood flow is restored, i.e.,
myocardial stunning. However, after a single,
relatively short episode of ischemia with
potential duration and therefore may promote
re-entrant arrhythmias such as ventricular
tachycardia.
From the above discussion, it is apparent that
ST segment changes will be the diagnostic hall-

mark of ischemia to be observed during non-
invasive testing. The classical test used is the
exercise stress test.
62
During dynamic physical
exercise on a treadmill or bicycle ergometer,
heart rate and blood pressure increase as cardiac
work increases. Ischemia is precipitated as dis-
cussed earlier in this chapter. The 12-lead ECG is
continuously monitored for ST segment depres-
sion.In addition to ST segment depression,other
changes may occur during exercise that are
indicative of myocardial ischemia and may aid
interpretation of the test. A decrease in systolic
blood pressure, or a failure to increase as
expected, may indicate widespread myocardial
ischemia. Chest pain may also occur, thus repro-
ducing the clinical manifestation of angina.
Whereas induction of angina and ST segment
depression are the main diagnostic elements of
the exercise stress test, these are relatively late
events in the ischemic cascade. This has two
implications. First, the stress test may fail to
diagnose ischemia because of the relative insen-
sitivity of these abnormalities compared with
earlier changes such as abnormalities in region-
al function or perfusion. This may explain
disparate results between tests. Second, other
noninvasive tests may be positive without
necessarily reproducing chest pain or ST depres-

sion, but when they do occur, they often suggest
significant disease.
6. Consequences of Ischemia
The discussion above has mainly centered on the
findings during acute ischemia or on patients
with chronic angina. Other ischemic syndromes
have been recognized in recent years and are
briefly reviewed in this section.
6.1 Myocardial Hibernation and Stunning
The phenomenon of myocardial stunning is
described as transient ventricular systolic dys-
function persisting for some time after ischemia.
It is discussed above (section 5.2). Myocardial
hibernation is a chronic ischemic syndrome. It is
identified as resting left ventricular contractile
Principles of Pathophysiology 11